Substituted [1H-imidazol-5-ylialkanoic acids having angiotension II receptor antagonist activity

ABSTRACT

PCT No. PCT/US91/05391 Sec. 371 Date Jan. 29, 1993 Sec. 102(e) Date Jan. 29, 1993 PCT Filed Jul. 30, 1991 PCT Pub. No. WO92/02510 PCT Pub. Date Feb. 20, 1992.Angiotensin II receptor antagonists having the formula:    &lt;IMAGE&gt;   which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.

The present invention relates to new substituted [imidazol-5-yl]alkanoicacids which are angiotensin II receptor antagonists and are useful inregulating hypertension induced or exacerbated by angiotensin II and inthe treatment of congestive heart failure, renal failure, and glaucoma.This invention also relates to pharmaceutical compositions containingsubstituted [imidazol-5-yl]alkanoic acids and methods for using thesecompounds as antagonists of angiotensin II, as antihypertensive agentsand as agents for treating congestive heart failure, renal failure, andglaucoma.

BACKGROUND OF THE INVENTION

The class of peptide pressor hormone known as angiotensin is responsiblefor a vasopressor action that is implicated in the etiology ofhypertension in man. Inappropriate activity of the renin-angiotensinsystems appears to be a key element in essential hypertension,congestive heart failure and in some forms of renal disease. In additionto a direct action on arteries and arterioles, angiotensin II (AII),being one of the most potent endogenous vasoconstrictors known,stimulates the release of aldosterone from the adrenal cortex.Therefore, the renin-angiotensin system, by virtue of its participationin the control of renal sodium handling, plays an important role incardiovascular homostasis.

Interruption of the renin-angiotensin system with converting enzymeinhibitors, such as captopril, has proved to be clinically useful in thetreatment of hypertension and congestive heart failure (Abrams, W. B.,et al, (1984), Federation Proc., 43, 1314). The most direct approachtowards inhibition of the renin-angiotensin system would block theaction of AII at the receptor. Compelling evidence suggests that AIIalso contributes to renal vasoconstriction and sodium retention that ischaracteristic of a number of disorders such as heart failure, cirrhosisand complications of pregnancy (Hollenberg, N. K., (1984), J. Cardiovas.Pharmacol., 6, S176). In addition, recent animal studies suggest thatinhibition of the renin-angiotensin system may be beneficial in haltingor slowing the progression of chronic renal failure (Anderson, S., etal, (1985), J. Clin Invest., 76, 612). Also, a recent patent application(South African Patent Application Number 87/01,653) claims that AIIantagonists are useful as agents for reducing and controlling elevatedintraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and antagonize the actionof the hormone AII, and are therefore useful in regulating andmoderating angiotensin-induced hypertension, congestive heart failure,renal failure, glaucoma, and other disorders attributed to the actionsof AII. When compounds of this invention are administered to mammals,the elevated blood pressure due to AII is reduced, and othermanifestations based on AII intercession are minimized and controlled.Compounds of this invention are also expected to inhibit diureticactivity.

Recognition of the importance of blocking and inhibiting the actions ofAII has stimulated other efforts to synthesize antagonists of AII. Thefollowing references have disclosed imidazole derivatives which aredescribed as having AII blocking activity and useful as hypotensiveagents.

U.S. Pat. No. 4,340,598 discloses substituted imidazol-5-yl alkanoicacids, and amido and lower-alkyl ester derivatives thereof, of theformula: ##STR2## wherein R¹ is lower alkyl or phenylC₁₋₂ alkyloptionally substituted with halogen or nitro; R² is lower alkyl,cycloalkyl, or phenyl optionally substituted; one of R³ and R⁴ is--(CH₂)_(n) COR⁵, where R⁵ is amino lower alkoxy or hydroxy and n is0-2, and the other of R³ and R⁴ is hydrogen or halogen. Examples include1-benzyl-2-n-butyl-4-chloroimidazole-5-acetamide and1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid.

U.S. Pat. No. 4,355,040 discloses substituted 1-benzylimidazol-5-ylacetic acid derivatives having the formula: ##STR3## wherein R¹ is loweralkyl, cycloalkyl, or phenyl optionally substituted; X¹, X² and X³ areeach hydrogen, halogen, nitro, amino, lower alkyl, lower alkoxy,benzyloxy, or hydroxy; Y is halogen and R² is hydrogen or lower alkyl. Acompound specifically disclosed is1-(2-chlorobenzyl)-2-n-butyl-4-chloro-imidazole-5-acetic acid.

European Patent Application 103,647 discloses substituted1-benzyl-2-phenyl-4-chloroimidazole-5-yl acetic acid derivatives of theformula: ##STR4## wherein R is lower alkyl. Specifically, the disclosureincludes4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid.

European Patent Application 253,310 discloses substituted1-aralkylimidazoles having the general formula: ##STR5## wherein R¹includes groups such as phenyl optionally substituted oradamantylmethyl; R² includes groups such as hydrogen, halo, NO₂, C₁₋₄alkyl, or C₁₋₄ alkoxy; R³ is hydrogen, halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy;R⁶ includes groups such as C₂₋₁₀ alkyl, C₃₋₁₀ alkenyl, C₃₋₈ cycloalkyl,benzyl optionally substituted or Z(CH₂)₁₋₅ --R⁵, wherein Z is O or S andR⁵ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or alkenyl; R⁷ is hydrogen,halo, NO₂, CF₃, or CN; and R⁸ includes groups such as C₁₋₁₀ alkanoicacids, esters and amides and alkyl N-alkyl carbamates. Examples include2-n-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid and1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-4-chloro-5(dimethylcarbamoyl)imidazole.

DESCRIPTION OF THE INVENTION

The compounds of the present invention that are blockers of angiotensinII receptors are represented by the following Formula (I): ##STR6## inwhich:

R¹ is adamantylmethyl, or phenyl, biphenyl, or naphthyl, with each arylgroup being unsubstituted or substituted by one to three substituentsselected from Cl, Br, F, I, C₁₋₆ alkyl nitro, CO₂ R⁸, tetrazol-5-yl,C₁₋₆ alkoxy, hydroxy, SC₁₋₄ alkyl, SO₂ NHR⁸, NHSO₂ R⁸, SO₃ H CONR⁸ R⁸,CN, SO₂ C₁₋₄ alkyl, or C_(n) F_(2n+1), wherein n is 1-3;

R² is C₂₋₁₀ alkyl, C₃₋₁₀ alkenyl, C₃₋₁₀ alkynyl, C₃₋₆ cycloalkyl, or(CH₂)₀₋₈ -phenyl unsubstituted or substituted by one to threesubstituents selected from C₁₋₆ alkyl, nitro, Cl, Br, F, I, hydroxy,C₁₋₆ alkoxy, NR⁸ R⁸, CO₂ R⁸, CN, or CONR⁸ R⁸ ;

X is a single bond, S, or O;

R³ is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, CO₂ R⁸, CONR⁸ R⁸, NO₂,or C_(n) F_(2n+1), wherein n is 1-3;

q is 0 to 4;

m is 0 to 2;

R⁴ is H or C₁₋₆ alkyl;

z is 0 to 1;

R⁵ is C₃₋₆ alkyl, C₃₋₆ alkenyl, phenyl-Y-, 2- or 3- thienyl-Y-, 2-or3-furyl-Y-, 2-, 3-, or 4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-,imidazolyl-Y-, pyrazolyl-Y-, thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-,with each aryl ring being unsubstitued or substitued by C₁₋₆ alkyl, Cl,Br, F, I, C₁₋₆ alkoxy, NR⁸ R⁸, CO₂ R⁸, or CONR⁸ R⁸ ;

Y is a single bond or C₁₋₆ alkyl which is branched or unbranched;

R⁶ is CO₂ R⁸, CONR⁸ R⁸, or tetrazol-5-yl;

R⁷ is H, CO₂ R⁸, or C₁₋₆ alkyl; and

each R⁸ independently is hydrogen, C₁₋₆ alkyl, or (CH₂)₀₋₄ phenyl;

or a pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are represented by Formula (I)when:

R¹ is phenyl unsubstituted or substituted by one to three substituentsselected from chloro, fluoro, trifluoromethyl, nitro, methyl, methoxy,hydroxy, sulfonamido, cyano, carboxy, carboC₁₋₆ alkoxy, carbamoyl, ortetrazol-5-yl;

q is one;

X is a single bond or S;

R² is C₂ -C₈ alkyl;

R³ is hydrogen, chloro, fluoro, or C_(n) F_(2n+1), wherein n is 1-3; and

R⁵ is C₄₋₆ alkyl, phenyl-CH₂ --, or thienyl-CH₂ --, with each aryl ringbeing unsubstituted or substituted by methyl, methoxy, or chloro;

or a pharmaceutically acceptable salt thereof.

As used herein, the terms alkyl, alkenyl, alkoxy, and alkynyl meancarbon chains which are branched or unbranched with the length of thechain determined by the descriptor preceding the term. Included withinthe scope of Formula (I) compounds are the racemic mixtures as well asthe single enantiomers encompassed by the genus of Formula (I).

Particular compounds of the invention include, but are not limited to,the following:

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-butyl-1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienylmethyl) propanoic acid,

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(4-chlorobenzyl)propanoic acid,

3-[2-n-butyl-1-{4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoicacid,

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoicacid,

3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

(2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-3-methylpropanoic acid,

3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoic acid,

2-carboethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid,

3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-n-pentylpropanoicacid,

3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-(2-propenyl)propionic acid,

2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylmalonicacid,

methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropionate,

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoicacid, and

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid;

or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions comprising apharmaceutical carrier and an effective amount of a compound of Formula(I) .

Also included in the present invention are methods for antagonizingangiotensin II receptors which comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I). Methodsof treating hypertension, congestive heart failure, renal failure, andglaucoma by administering these compounds are also included in thisinvention.

The compounds of this invention and of the pharmaceutical compositionsand methods of this invention are prepared by procedures describedherein and illustrated by the examples. Reagents, protecting groups andfunctionality on the imidazole and other fragments of the molecule mustbe consistent with the proposed chemical transformations. Steps in thesynthesis must be compatible with the functional groups and theprotecting groups on the imidazole and other parts of the molecule.##STR7##

Scheme I shows the synthesis of Formula (I) compounds wherein X is S, R¹is a phenyl unsubstituted or substituted by a group Y, hereinbelowdefined, R² is as defined for Formula (I) compounds, R³ is H, m and zare each O, q is one, R⁷ is hydrogen, and R⁶ is CO₂ H or CO₂ C₁₋₆ alkyl.According to Scheme I, formula (1) benzylamines, which are unsubstitutedor substituted by one to three Y substituents selected from halo, C₁₋₆alkyl, C₁₋₆ alkoxy, CN, NO₂, CF₃, CO₂ C₁₋₆ alkyl, SC₁₋₄ alkyl, or SO₂C₁₋₄ alkyl, are reacted with a thiocyanate, such as ammoniumthiocyanate, in a suitable solvent, such as water, at a temperature ofabout 40° C. to about 100° C., preferably at about 80° C. to giveformula (2) thiourea compounds. The free thio group of the formula (2)compounds is reacted with a halo-R⁹ compound, wherein R⁹ is C₂₋₁₀ alkyl,C₃₋₁₀ alkenyl, C₃₋₁₀ alkynyl, C₃₋₆ cycloalkyl, or an optionallysubstituted (CH₂)₀₋₈ phenyl, preferably propylbromide, in a suitablesolvent, such as acetonitrile, at a temperature of about 50° C. to about80° C., preferably at about 80° C., to give formula (3) compounds.Formation of the imidazole nucleus is accomplished by reacting theformula (3) compounds with a C₁₋₆ alkyl 3-formyl-2-(R⁵-substituted)-2-propanoate of formula (4) which had been synthesized byreacting (triphenylphosphoranylidene)acetaldehyde with an R⁵ --CO--CO₂C₁₋₆ alkyl compound. These formula (5) ester imidazoles, which areFormula (I) compounds, are hydrolyzed to formula (6) acids using base,such as potassium, sodium, or lithium hydroxide, in a suitable solventsystem, such as aqueous C₁₋₄ alkanols or diglyme, or aqueous acid, suchas aqueous hydrochloric acid. Formula (6) compounds are Formula (I)compounds. ##STR8##

Scheme II shows an alternate synthesis of Scheme I, formula (6)compounds. According to Scheme II, Scheme I, formula (1 ) benzylaminesare condensed with di-C₁₋₆ alkyl 2,2-di-C₁₋₆ alkoxyethylidene malonatesof formula (7) in a suitable solvent, such as ethanol, to give formula(8) compounds. The formula (7) malonates are prepared by reactingdi-C₁₋₆ alkyl oxomalonates with (triphenylphosphoranylidene)acetaldehydein a suitable solvent, such as toluene, followed by acetal formationwith tri-C₁₋₆ alkyl orthoformate in the presence of strong acid, such asp-toluenesulfonic acid, and a water-scavening agent, such as 3Amolecular sieves. Imidazole formation is accomplished by reaction of theformula (8) intermediates with a thiocyanate, such as potassiumthiocyanate, in aqueous hydrochloric acid solution and an organicsolvent, such as a C₁₋₄ alkyl alcohol, to give formula (9) compounds.The free thio group of the formula (9) imidazoles is reacted with ahalo-R⁹ compound, wherein R⁹ is as defined hereinabove, in a suitablesolvent such as acetonitrile, at a temperature of about 50° C. to about80° C., preferably at about 80° C., to give formula (10) compounds. Themalonate compounds of formula (10) are alkylated with a R⁵ -halide,-acetate, or -sulfonate, such as benzyl bromide, in the presence of asuitable base, such as alkali metal alkoxide, for example, sodiumethoxide, in a suitable solvent, such as a C₁₋₄ alkyl alcohol, to giveformula (11) compounds. Hydrolysis and concomitant decarboxylation ofthe formula (11) malonates is carried out with aqueous base, forexample, aqueous sodium carbonate solution, in a suitable solvent, suchas a C₁₋₄ alkyl alcohol at a temperature of about 60° C. to about 100°C., preferably at about 80° C., to give formula (6) acid compounds.##STR9##

Scheme III outlines the synthesis of Formula (I) compounds in which the2-position substituent is R² S, m and q are 1, and z is 0. Formula (1)benzylamines, hereinbefore described, are alkylated with a C₁₋₄ alkylchloroacetate, for example, methyl chloroacetate, in the presence of abase, such as triethylamine, in a suitable solvent, such asdimethylformamide. The resulting alkylaminoalkyl ester compounds offormula (12) are N-formylated with formic acid in the presence of asuitable solvent, such as xylene, to give formula (13) compounds.Formula (14) compounds are formed by C-formylation of the carbon alphato both the amino and the ester groups of the formula (13) compounds ina reaction with an alkyl formate, such as methyl formate, in thepresence of an alkali metal halide, such as sodium hydride, in asuitable solvent, such as tetrahydrofuran. Reaction of this intermediatewith a thiocyanate, preferably potassium thiocyanate in aqueoushydrochloric acid solution, and an organic solvent, such as C₁₋₄alkanol, produces 1-R¹ CH₂ -2-mercapto-5-alkanoate ester imidazoles(15). The free thio group of formula (15) compounds is reacted with ahalo-R⁹ compound, wherein R⁹ is as described previously, in the presenceof a suitable base, such as sodium carbonate, in an appropriate solvent,such as ethyl acetate, to give 1-R¹ CH₂ -2-R² S-5-alkanoate esterimidazoles (16). The hydroxymethyl imidazoles of formula (17) areprepared from formula (16) compounds by reduction with an appropriatereagent, such as diisobutyl aluminum hydride, in a suitable solvent,such as tetrahydrofuran, at a temperature of about -78° C. to about 25°C. preferably at about -10° C. The formula (18) chloromethyl compoundsare prepared by reacting formula (17) hydroxymethyl compounds with ahalogenating agent, such as thionyl chloride. Reaction of formula (18)compounds with a di-C₁₋₂ alkyl R⁵ -malonate, wherein R⁵ is as definedfor Formula (I), such as diethyl 2-thienylmethylmalonate, which had beenpre-treated with a deprotonating agent, such as sodium hydride, yieldsformula (19) compounds. Optionally, formula (19) compounds, wherein R⁷is H, are alkylated with a C₁₋₄ alkyl halide, such as methyl iodide, togive the formula (19) compounds wherein R⁷ is C₁₋₆ alkyl. Formula (20)compounds, which are Formula (I) compounds, are prepared from formula(19) di-ester compounds using strong aqueous base, such as aqueouspotassium hydroxide solution, in a suitable organic solvent, such asmethanol or ethanol, at reflux temperatures.

Alternatively, formula (19) compounds are de-esterified andde-carboxylated in a stepwise fashion. For example, one of the estergroups of a formula (19) imidazole is removed using mild aqueous base,such as aqueous sodium bicarbonate solution, in a suitable organicsolvent, such as methanol or ethanol, to give Formula (I) compounds,wherein one of R⁷ or R⁶ is CO₂ C₁₋₆ alkyl and the other is CO₂ H. Thesehalf-acid, half-ester compounds are de-carboxylated, for example, byheating the compound neat at a temperature of about 120° C. to about180° C., preferably at about 130° C. to about 170° C. Formula (20)compounds are prepared from this mono-ester intermediate using aqueousbase, such as aqueous sodium or potassium hydroxide solution, in asuitable organic solvent, such as methanol or ethanol.

Formula (I) compounds wherein m is 2 are prepared using formula (10)imidazole compounds as intermediates. In this synthesis,hydrolysis/decarboxylation of the formula (10) compounds is carried asdescribed for the conversion of formula (11) to formula (6) compounds.This acid is esterified using conventional techniques, for example,stirring the acid in methanol saturated with hydrochloric acid.Reduction of the ester to the 2-hydroxyethyl derivative is accomplishedusing a suitable hydride reagent, such as diisobutylaluminum hydride, inan inert organic solvent, such as tetrahydrofuran, at a temperature ofabout -78° C. to about 25° C. Conversion to the chloroethyl imidazolestaxes place by reacting the hydroxyethyl intermediates with a suitablehalogenating agent, such as thionyl chloride. Formula (I) compoundswherein m is 2 are prepared as described in Scheme III, replacingformula (18) chloromethyl compounds with the above-prepared chloroethylintermediates. ##STR10##

The starting materials, 2-R² X-imidazoles of formula (21) are known tothe art (J. Org. Chem. 45:4038, 1980) or are synthesized by knownprocedures. For example, imidazole is converted to 2-n-butylimidazole byreacting imidazole with triethylorthoformate and p-toluenesulfonic acidto give 1-diethoxyorthoamide imidazole and then treating with n-butyllithium to give the 2-lithium derivative of the orthoamide andalkylating with n-butyl iodide in a suitable solvent, such astetrahydrofuran.

According to Scheme IV, the 1-R¹ (CH₂)_(q) -group is incorporated ontothe 2-R² X-imidazole of formula (21) by known procedures, for example,by reaction with an R¹ -CH₂ halide, mesylate or acetate, such as2-chlorobenzyl bromide, in a suitable solvent, such asdimethylformamide, in the presence of suitable acid acceptor, such assodium alkylate, potassium or sodium carbonate, or a metal hydride,preferably sodium hydride, at a reaction temperature of about 25° C. toabout 100° C., preferably at about 50° C. The resulting 1-R¹ (CH₂)_(q)-2-R² X-imidazole of formula (22) is hydroxymethylated in the5-position, for example, by reacting with formaldehyde in the presenceof sodium acetate in acetic acid to provide the 1-R¹ (CH₂)_(q) -2-R²X-5-hydroxymethylimidazole intermediates of formula (23).

Alternatively, the 1-R¹ (CH₂)_(q) -2-R² X-5- hydroxymethylimidazoleintermediates are prepared by reacting an imido ether, R²X-C(═NH)-O-alkyl, such as valeramidine methyl ether, withdihydroxyacetone in liquid ammonia under pressure to give 2-R²X-5-hydroxymethylimidazole. This intermediate is reacted with aceticanhydride to give 1-acetyl-5-acetoxy-methyl-2-R2X- imidazole. Thediacetate intermediate is N-alkylated, for example, using 2-chlorobenzyltriflate, and the resulting 1-R¹ (CH₂)_(q) -2-R²X-5-acetoxymethylimidazole is treated with aqueous base, such as 10%sodium hydroxide solution, to give the 1-R¹ (CH₂)_(q) -2-R²X-5-hydroxymethylimidazole intermediate of formula (23).

The formula (23) hydroxymethyl compounds are converted to thecorresponding chloromethyl compounds of formula (24) using ahalogenating agent, such as thionyl chloride. Formula (I) compounds offormula (25) are prepared from formula (24) imidazoles following theprocedures described in Scheme III, replacing formula (18) chloromethylcompounds with formula (24) chloromethyl imidazoles. ##STR11##

Scheme V shows an alternate synthesis for the preparation of Formula (I)compounds wherein z is 0, m is 1, R⁶ is CO₂ R⁸, and R¹, R², X, R⁵, R⁸,and q are as defined in Formula (I). According to Scheme V, thehydroxymethyl group of the Scheme IV formula (23) intermediate isoxidized to an aldehyde by treatment with a suitable reagent, such asanhydrous chromic acid-silica gel in tetrahydrofuran or, preferably,with activated maganese dioxide, in a suitable solvent, such as benzeneor toluene, or preferably methylene chloride, at a temperature of about25° C. to about 140° C., preferably at about 25° C., to give formula(26) compounds. These 1-R¹ (CH₂)_(q) -2-R² X-imidazol-5-carboxaldehydesare reacted with an appropriate phosphonate, such as diethyl2-n-butyl-2phosphonopropionate. The phosphonates are prepared, forexample, from trialkyl phosphonoacetates by alkylation with anappropriate halide, mesylate, or acetate in the presence of a suitablebase, such as sodium hydride, in a suitable solvent, preferably glyme,at a reaction temperature of about 25° C. to about 110° C., preferablyat about 55° C. The reaction of the imidazol-5-carboxaldehydes with thephosphonates is performed in the presence of a suitable base, such as ametal alkoxide, lithium hydride or preferably sodium hydride, in asuitable solvent, such as ethanol, methanol, ether, dioxane,tetrahydrofuran, or preferably glyme, at a reaction temperature of about10° C. to about 50° C. preferably at about 25° C., to provide a variablemixture of trans and cis, e.g., (E) and (Z), 1-R¹ (CH₂)_(q) -2-R²X-5-CH═C(R⁵)-(COOalkyl)-imidazoles of formula (27). Reduction of thevinyl group of formula (27) compounds is accomplished using, forexample, hydrogen in the presence of a catalyst, such as platinum oxideor palladium on carbon, in a suitable solvent, such as ethanol, to giveformula (28) compounds. The formula (28) esters are hydrolyzed to theacids of formula (29) using base, such as potassium hydroxide, lithiumhydroxide or sodiumhydroxide, in a suitable solvent system, such asaqueous alcohols or glyme.

Alternately, Formula (I) compounds are prepared from Scheme V, formula(26), compounds. The formula (26) aldehydes are reacted with a di-C₁₋₂alkyl malonate, such as diethyl malonate, in the presence of a base,such as piperidine. The resulting vinyl diester compounds are reduced tothe corresponding saturated analogs using, for example, sodiumborohydride in an appropriate solvent, such as ethanol. Reaction of thisintermediate with a base, such as sodium hydride, followed by reactionwith an R⁵ -halide, such as 4-chlorobenzyl chloride, yields formula(19)-type compounds. Formula (I) compounds are prepared by subsequenthydrolysis/decarboxylation as described hereinbefore.

Formula (I) compounds wherein R⁴ is C₁₋₆ alkyl are prepared by thefollowing procedure. The 1-R¹ (CH₂)_(q) -2-R²X-imidazol-5-carboxaldehydes, prepared as described above, are convertedto the corresponding alcohols with an organometallic derivative orGrignard reagent, preferably methyl lithium, in a suitable solvent, suchas tetrahydrofuran. The alcohol is oxidized, for example, using maganesedioxide to give the ketone. The olefinic esters are prepared from theketone by reaction with appropriate phosphonates to give the (E) and/or(Z) isomers. The saturated acid compounds are prepared from the estersby catalytic hydrogenation and alkaline hydrolysis as describedpreviously.

Alternatively, the 1-R¹ (CH₂)_(q) -2-R² X-imidazol-5-carboxaldehydes offormula (26) are prepared by the following procedure. Starting 2-R²X-imidazol-5-carboxaldehydes are reacted with an N-alkylating protectingreagent, such as chloromethyl pivalate (POM-Cl), in the presence of abase, such as potassium carbonate, in a suitable solvent, such asdimethylformamide, at a temperature of about 20° C. to about 50° C.,preferably at about 25° C., to give N-alkylation (e.g., POM-derivation)on the least hindered nitrogen atom of the imidazole nucleus. The 1-R¹(CH₂)_(q) -group is incorporated onto the imidazole with anappropriately substituted halide compound, such as methyl4-bromomethyl-3-chlorobenzoate, at a temperature of about 80° C. toabout 125° C., preferably at about 100° C. The protecting group on the3-nitrogen of the imidazole ring is removed by base-hydrolysis, forexample, using a biphasic mixture of ethyl acetate and aqueous sodiumcarbonate, to give 1-R¹ (CH₂)_(q) - 2-R² X-imidazole-5-carboxaldehydecompounds. The Formula (I) compounds can be prepared from these5-carboxaldehyde compounds by the methods described above. ##STR12##

Scheme VI shows the synthesis of Formula (I) compounds wherein z is 1 mis 0 R⁶ is CO₂ R⁸ and R¹, R², X, R⁴, R⁵, R⁸, and q are as defined inFormula (I) . According to Scheme VI, the 2-R² X-imidazole startingmaterials of formula (21) are reacted with trimethylsilylethoxymethyl(SEM) chloride to give formula (30) 1-(trimethylsilyl)ethoxymethyl-2-R²X-imidazole. The reaction is carried out, for example, in the presenceof sodium hydride in a solvent, such as dimethylformamide. The formula(31) 5-tributyltin derivatives are prepared by lithiation with, forexample, butyllithium in a suitable solvent, preferably diethyl ether,followed by treatment of the lithio imidazole derivative with atributyltin halide, preferably tributyltin chloride, at about -10° C. toabout 35° C. preferably at about 25° C. The 1-SEM-2-R²X-5-tributyltinimidazole of formula (31) is coupled with ana,b-unsaturated acid ester having a leaving group on the b-position,such as a halide or trifluoromethanesulfonyloxy group, for example,BrCR⁴ ═C(R⁵)(COOalkyl), in the presence of a phosphine ligand, such asbis(diphenylphosphino)propane or triphenylphosphine and a palladium (II)compound, or preferably tetrakis(triphenylphosphine)palladium(O), withor without a base, such as tributylamine, at a temperature of about 50°C. to about 150° C., preferably at about 120° C., to give formula (32)compounds. Reduction of vinyl group of formula (32) compounds isaccomplished using, for example, hydrogen in the presence of a catalyst,such as platinum oxide or palladium on carbon, in a suitable solvent,such as ethanol, to give formula (33) compounds. The 1-SEM group of theformula (33) imidazoles is hydrolyzed with acid, for example, aqueoushydrochloric acid, in a suitable alcoholic solvent, such as methanol orethanol. The 1-unsubstituted imidazole derivatives are converted to the1-t-butoxycarbonyl (t-BOC) imidazoles with di-t-butyl dicarbonate(Hoppe-Seyler's Z. Physiol. Chem., (1976), 357, 1651) to give formula(34) compounds. The t-BOC esters are alkylated and hydrolyzed with, forexample, 2-chlorobenzyl-O-triflate, in a suitable solvent, preferablymethylene chloride, to afford the 1-R¹ -(CH₂)_(q) -imidazole derivatives(esters) of formula (35). The formula (36) acid compounds are preparedfrom formula (35) esters using base hydrolysis as described previously.

Alternately, Formula (I) compounds wherein the alkylene bridge at the5-position of the imidazole ring is defined as m equal-to 0-2 areprepared from the alkanoic acid ester compounds described in U.S. Pat.No. 4,340,598. These esters are reduced to the corresponding alcoholsusing a suitable reagent such as diisobutyl aluminum hydride, in anappropriate solvent, such as tetrahydrofuran, at a temperature of about-78° C. to about 25° C., preferably at less than about -10° C. Formula(I) compounds are prepared from the resulting alcohol compoundsfollowing the procedures described in Scheme III (17-20).

Compounds of Formula (I) in which the R¹ substituent is substituted byhydroxy are formed from Formula (I) compounds in which the R¹ group issubstituted by C₁₋ C₄ alkoxy using an ether-cleaving reagent, such asboron tribromide or hydrobromic acid.

Compounds of Formula (I) in which the R¹ substituent is substituted bycarboxy are formed from Formula (I) compounds in which the R¹ group issubstituted by CO₂ C₁ -C₄ alkyl using basic hydrolysis, such as aqueoussodium or potassium hydroxide, in methanol or ethanol, or using acidichydrolysis, such as aqueous hydrochloric acid.

Compounds of Formula (I) in which the R substituent is substituted by atetrazol-5-yl group are prepared from the corresponding carboxycompounds. For example, Formula (I) acid compounds are reacted with ahalogenating agent, such as thionyl chloride, in a suitable solvent, forexample benzene, to give the corresponding acid halide compounds. Theacid halides are then converted to primary amide compounds in a reactionwith concentrated ammonia. Subsequent dehydration of the amides withoxalyl chloride/dimethylformamide in acetonitrile/dimethylformamideyields the nitrile compounds, which are the immediate precursors to theFormula (I) tetrazole compounds. Tetrazole formation is accomplished byreacting the nitriles with azide, preferably aluminum azide prepared insitu by the reaction of sodium azide with aluminum chloride, in asuitable solvent, for example tetrahydrofuran. The Formula (I) compoundsin which R⁶ is CO₂ H are prepared from these Formula (I) tetrazole estercompounds by basic hydrolysis as described above.

Compounds of Formula (I) in which R⁶ is tetrazol-5-yl are prepared fromthe corresponding carboxy compounds using the procedure hereinbeforedescribed.

Pharmaceutically acceptable acid addition salts of compounds of Formula(I) are formed with appropriate organic or inorganic acids by methodsknown in the art. For example, the base is reacted with a suitableinorganic or organic acid in an aqueous miscible solvent such asethanol, with the salt being isolated by removing the solvent or in anaqueous immiscible solvent, when the acid is soluble therein, such asethyl ether or chloroform, with the desired salt separating directly orisolated by removing the solvent. Representative examples of suitableacids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, aspattic, stearic,palmitic, iraconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,hydrochloric, hydrobromic, sulfuric, cyclohexylsulfonic, phosphoric andnitric acids.

Pharmaceutically acceptable base addition salts of compounds of Formula(I) which have an acidic group are prepared by known methods fromorganic and inorganic bases, including nontoxic alkali metal andalkaline earth bases, for example, calcium, lithium, sodium, andpotassium hydroxide; ammonium hydroxide, and nontoxic organic bases,such as triethylamine, butylamine, piperazine, meglumine, choline,diethanolamine, and tromethamine.

Angiotensin II antagonist activity of the compounds of Formula (I) isassessed by in vitro and in vivo methods. In vitro antagonist activityis determined by the ability of the compounds to compete withI-angiotensin II for binding to vascular angiotensin II receptors and bytheir ability to antagonize the contractile response to angiotensin IIin the isolated rabbit aorta. In vivo activity is evaluated by theefficacy of the compounds to inhibit the pressor response to exogenousangiotensin II in conscious rats and to lower blood pressure in a ratmodel of renin dependent hypertension.

Binding

The radioligand binding assay is a modification of a method previouslydescribed in detail (Gunther et al., Circ. Res. 47:278, 1980). Aparticular fraction from rat mesenteric arteries is incubated in Trisbuffer with 80 pM of ¹²⁵ I-angiotensin II with or without angiotensin IIantagonists for 1 hour at 25° C. The incubation is terminated by rapidfiltration and receptor bound ¹²⁵ I-angiotensin II trapped on the filteris quantitated with a gamma counter. The potency of angiotensin IIantagonists is expressed as the IC₅₀ which is the concentration ofantagonist needed to displace 50% of the total specifically boundangiotensin II.

Aorta

The ability of the compounds to antagonize angiotensin II inducedvasoconstriction is examined in the rabbit aorta. Ring segments are cutfrom the rabbit thoracic aorta and suspended in organ baths containingphysiological salt solution. The ring segments are mounted over metalsupports and attached to force displacement transducers which areconnected to a recorder. Cumulative concentration response curves toangiotensin II are performed in the absence of antagonist or following a30-minute incubation with antagonist. Antagonist disassociationconstants (K_(B)) of compounds of the invention are then calculated.

Inhibition of pressor response to angiotensin II in conscious rats

Rats are prepared with indwelling femoral arterial and venous cathetersand a stomach tube (Gellai et al., Kidney Int. 15:419, 1979). Two tothree days following surgery the rats are placed in a restrainer andblood pressure is continuously monitored from the arterial catheter witha pressure transducer and recorded on a polygraph. The change in meanarterial pressure in response to intravenous injections of 250 mg/kgangiotensin II is compared at various time points prior to and followingthe administration of the compounds intravenously or orally at doses of3 to 300 mg/kg. The dose-of compound needed to produce 50% inhibition ofthe control response to angiotensin II (IC₅₀) is used to .estimate thepotency of the compounds.

Antihypertensive activity

The antihypertensive activity of the compounds is measured by theirability to reduce mean arterial pressure in conscious rats maderenin-dependent hypertensive by ligation of the left renal artery(Cangiano et al., J. Pharmacol. Exp. Ther. 208:310, 1979). Renal arteryligated rats are prepared with indwelling catheters as described above.Seven to eight days following renal artery ligation, the time at whichplasma renin levels are highest, the conscious rats are placed inrestrainers and mean arterial pressure is continuously recorded prior toand following the administration of the compounds intravenously ororally.

The intraocular pressure lowering effects employed in this invention maybe measured by the procedure described by Watkins, et al., J. OcularPharmacol., 1 (2):161-168 (1985).

The compounds of Formula (I) are incorporated into convenient dosageforms, such as injectable preparations, or for orally active compounds,capsules or tablets. Solid or liquid pharmaceutical carriers areemployed. Solid carriers include starch, lactose, calcium sulfatedihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, and stearic acid. Liquid carriers include syrup,peanut oil, olive oil, saline, and water. Similarly, the carrier ordiluent may include any prolonged release material, such as glycerylmonostearate or glyceryl distearate, alone or with a wax. The amount ofsolid carrier varies but, preferably, will be from about 25 mg to about1 g per dosage unit. When a liquid carrier is used, the preparation willbe in the form of a syrup, elixir, emulsion, soft gelatin capsule,sterile injectable liquid, such as an ampoule, or an aqueous ornonaqueous liquid suspension.

For topical ophthalmologic administration, the pharmaceuticalcompositions adapted include solutions, suspensions, ointments, andsolid inserts. Typical pharmaceutically acceptable carriers are, forexample, water, mixtures of water and water-miscible solvents such aslower alkanols or vegetable oils, and water soluble ophthalmologicallyacceptable non-toxic polymers, for example, cellulose derivatives suchas methyl cellulose. The pharmaceutical preparation may also containnon-toxic auxiliary substances such as emulsifying, preserving, wetting,and bodying agents, as for example, polyethylene glycols; antibacterialcomponents, such as quarternary ammonium compounds; bufferingingredients, such as alkali metal chloride; antioxidants, such as sodiummetabisulfite; and other conventional ingredients, such as sorbitanmonolaurate.

Additionally, suitable ophthalmic vehicles may be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems.

The pharmaceutical preparation may also be in the form of a solidinsert. For example, one may use a solid water soluble polymer as thecarrier for the medicament. Solid water insoluble inserts, such as thoseprepared from ethylene vinyl acetate copolymer, may also be utilized.

The pharmaceutical preparations are made following conventionaltechniques of a pharmaceutical chemist involving mixing, granulating,and compressing, when necessary, for tablet forms, or mixing, fillingand dissolving the ingredients, as appropriate, to give the desiredoral, parenteral, or topical products.

Doses of the compounds of Formula (I) in a pharmaceutical dosage unit asdescribed above will be an efficacious, nontoxic quantity selected fromthe range of 0.01-200 mg/kg of active compound, preferably 1-100 mg/kg.The selected dose is administered to a human patient in need ofangiotensin II receptor antagonism from 1-6 times daily, orally,rectally, topically, by injection, or continuously by infusion. Oraldosage units for human administration preferably contain from 1 to 500mg of active compound. Lower dosages are used generally for parenteraladministration. Oral administration, is used when safe, effective andconvenient for the patient. Topical formulations contain the activecompound in an amount selected from 0.0001 to 0.1 (w/v%), preferablyfrom 0.0001 to 0.01. As a topical dosage unit form, an amount of activecompound from between 50 ng to 0.05 mg, preferably 50 ng to 5 μg, isapplied to the human eye.

The method of this invention of antagonizing angiotensin II receptors inmammals, including humans, comprises administering to a subject in needof such antagonism an effective amount of a compound of Formula (I). Themethod of this invention of producing antihypertensive activity and themethod of treating congestive heart failure, glaucoma, and renal failurecomprise administering a compound of Formula (I) to a subject in needthereof an effective amount to produce said activity.

The following examples illustrate preparation of compounds andpharmaceutical compositions of this invention. The examples are notintended to limit the scope of this invention as defined hereinabove andas claimed below.

EXAMPLE 12-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionicAcid (i) ethyl 3-formyl-2-methyl-2-propanoate

A solution of triphenylphosphoranylidene acetaldehyde (15.74 g, 0.0517mol) in dry toluene (80 mL) was added all at once to ethyl pyruvate(5.65 mL, 0.0517 mol). The solution was heated at 95° C. for 1 hour andthen concentrated to a syrup. Molecular distillation provided 2.1 g(29%) of the yellow, oily ethyl 3-formyl-2-methyl-2-propanoate.

(ii) 1-(2-chlorophenyl)methyl-2-propyl-2-thiopseudourea

A solution of 2-chlorobenzylamine hydrochloride (41 g, 0.23 mol) andammonium thiocyanate (19.28 g, 0.253 mol) in water (170 mL) was heatedon the steam bath for 18 hours. This mixture was concentrated in vacuo,and the residue was taken up in toluene (1 L) and azeotroped with aDean-Stark head. The residue was triturated with wet diethyl ether toprovide 27.6 g (60%) of 1-(2-chlorophenyl)methyl thiourea. The productwas recrystallized from ethanol; mp 120°-122° C.

A mixture of 1-(2-chlorophenyl)methyl thiourea (3 g, 14.9 mmol) andpropylbromide (13.5 g, 110 mmol) in acetonitrile (20 mL) was refluxedfor 5 hours. The solvent was evaporated, the residue was dissolved in200 mL of 50% water/ether and acidified with 48% hydrobromic acidsolution. The two phases were separated, the aqueous layer was washedwith ether and then the aqueous layer was basified with 10% sodiumcarbonate solution. The liberated product was extracted with diethylether, washed with water and brine, dried and concentrated to give1-(2-chlorophenyl)methyl-2-propyl-2-thiopseudourea (2.82 g, 78%); mp112°-114° C.

(iii) ethyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionate

A solution of 1-(2-chlorophenyl)methyl-2-propyl-2-thiopseudourea (3.42g, 14 mmol) and ethyl 3-formyl-2-methyl-2-propanoate (2 g, 14 mmol) inethanol (15 mL) was refluxed for 5 hours and then concentrated in vacuo.The crude product (5.2 g) was dissolved in ether and extracted with 2Naqueous hydrochloric acid solution (4x). The aqueous acid extracts werewashed with diethyl ether, and adjusted to pH 8.5 with solid sodiumcarbonate. The aqueous layer was extracted with ether and then driedover anhydrous sodium sulfate. The ether layer was concentrated to give1.9 g (37%) of an amber syrup. This was flash chromatographed oversilica gel with 3:2 cyclohexane/ethyl acetate to afford 0.75 g of ethyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionateas an oil.

(iv)2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionicacid

A solution of ethyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionate(0.71 g, 1.94 mmol) in water (10 mL) and methanol (5 mL) was treatedwith potassium carbonate (0.51 g, 3.7 mmol). The reaction mixture wasrefluxed on a steam bath for 2 hours, the methanol was evaporated, theaqueous layer was washed with diethyl ether, cooled in ice, and adjustedto pH 3.4 with aqueous hydrochloric acid solution. The resulting gummysolid was extracted into methylene chloride, washed with water, dried,and concentrated. The residue was triturated with diethyl ether to give2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionicacid; mp 170°-172° C.

EXAMPLE 22-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-3-phenylpropionicAcid (i) diethyl[1-{(2-chlorophenyl)methyl}amino-2,2-diethoxy]ethylmalonate

To a solution of diethyl ketomalonate (57.7 g, 0.33 mol) in dry toluene(800 mL) cooled in ice water was added portionwisetriphenylphosphoranylidene acetaldehyde (100.8 g, 0.33 mol) over aperiod of one hour. The mixture was then stirred an additional hour. Tothe cold solution was added triethyl orthoformate (110 mL, 0.662 mol),p-toluenesulfonic acid hydrate (4 g) and 3A molecular sieves (30 g). Themixture was heated in a hot water bath at 60° C. for 2 hours, cooled andthe suspension was filtered. The filtrate was concentrated, the residuewas dissolved in 3:2 hexane/diethyl ether, and then chilled. The solidwas separated, and the solution was concentrated to about 100 g of crudeproduct which was flash chromatographed over 800 g of silica gel,eluting with 3:2 hexane/diethyl ether to give 87.14 g (96%) of diethyl2,2-diethoxyethylidene malonate as a syrup.

This product (87.14 g, 0.318 mol) was dissolved in absolute ethanol (400mL) and treated rapidly with a solution of 2-chlorobenzylamine (44.9 g,0. 318 mol) in ethanol (200 mL). The mixture was stirred for 4 hours atambient temperature and then concentrated in vacuo to give 124.4 g ofcrude diethyl[1-{(2-chlorophenyl)methyl}-amino-2,2-diethoxy]ethylmalonate.

(ii) diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]malonate

Ice cold 1N aqueous hydrochloric acid solution (126 mL) was treated withpotassium thiocyanate (11.8 g, 0.121 mol). After 5 minutes, diethyl[1-{(2-chloro-phenyl)methyl/amino-2,2-diethoxy]ethylmalonate, (50 g,0.12 mol) in ethanol (300 mL) was added rapidly, and the solution washeated on a steam bath for 6 hours. The ethanol was evaporated, theproduct was extracted into methylene chloride, dried, and concentratedto about 40 g of crude diethyl[1-{(2-chlorophenyl)methyl}-2-thio-1H-imidazol-5-yl ]malonate. Thismaterial was used as is for the next reaction.

A solution of this product (4.03 g, 0.0106 mol) in acetonitrile (100 mL)was treated with n-propylbromide (25 mL) and refluxed for 18 hours. Thesolvent was removed under vacuum to provide the syrupy, crude diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]malonate (5.1g, 97%).

(iii) diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]phenyl-methylmalonate

To a solution of sodium ethoxide (0.0596 g, 2.59 mmol) in absoluteethanol (10 mL) was added a solution of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5yl]malonate (1.05g, 2.47 mmol) in absolute ethanol (5 mL). This mixture was stirred underargon for 10 minutes, then benzyl bromide (0.309 mL, 2.59 mmol) wasadded. The reaction mixture was stirred at 25° C. for 30 minutes, thenrefluxed for 18 hours. The cooled mixture was partitioned betweendiethyl ether/water. The ethereal phase was washed with brine, driedwith anhydrous sodium sulfate, and concentrated to 1.25 g of crudeproduct which was flash chromatographed over silica gel with 85:15methylene chloride/ethyl acetate to give 0.66 g (52%) of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-phenyl-methylmalonateas a syrup.

(iv)2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-3-phenyl-propionicacid

A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]phenylmethyl-malonate (0.66 g, 1.28 mmol),sodium carbonate (1.36 g, 1.28 mmol), ethanol (15 mL) and water (10mL)was refluxed on a steam bath for 18 hours. The mixture wasconcentrated to a small volume, some insolubles were filtered, theaqueous layer was washed with diethyl ether and then the aqueous phasewas adjusted to pH 3.4 with aqueous hydrochloric acid. The product wasextracted into methylene chloride, washed with water, dried andconcentrated to give 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-3-phenyl-propionic acid; mp 60°-63° C.

EXAMPLE 32-Carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoicAcid (i) 5-carboxymethyl-1-(2-chlorophenyl) methyl-2-thio-1H-imidazole

A solution of 2-chlorobenzylamine (14.2 g, 0.1 mol) and triethylamine(13.9 mL, 0.1 mol), in dimethylformamide (100 mL) was treated withmethyl chloroacetate (10.9 g, 0.1 mol), and the mixture was heated at50° C. for 3.5 hours. The cooled reaction mixture was diluted withdiethyl ether, the solids filtered and the concentrated filtrate wasflash chromatographed over silica gel with 6:5 hexane in ethyl acetateto provide 15.3 g (71%) of homogenous methyl2-[N-(2-chlorophenyl)methyl]aminoacetate. This product. (15.2 g, 0.071mol) in mixed xylenes (100 mL) was treated with 98% formic acid (2.74mL, 0.0711 mol) and the mixture was refluxed for 2.5 hours with aDean-Stark water separator. Evaporation gave 17.1 g (99%) of methyl2-[N-(2-chlorophenyl)methyl-N-formyl)aminoacetate. This formylatedproduct (17.0 g, 0.071 mol) was dissolved in methyl formate (13.3 mL,0.216 mol) and added dropwise to a sodium methoxide mixture prepared byadding sodium metal (1.79 g, 0.0778 g-atom) to tetrahydrofuran (325 mL)followed by slow addition of methanol (3.15 mL, 0.0778 mol). Thecombined mixture was stirred at room temperature for 18 hours, thenevaporated to dryness. This crude product was dissolved in 50% aqueousmethanol (200 mL), treated with charcoal, filtered and the solution wascooled in ice. Concentrated hydrochloric acid (14.3 mL of 12N, 0.171mol) was added slowly to this solution followed by a solution ofpotassium thiocyanate (8.6 g, 0.0885 mol) in water (20 mL). The mixturewas heated in an oil bath held at 90° C. for 2.5 hours, then cooled to-10° C. The precipitated solid was filtered, washed with coldethanol-water and dried at 60° C. to provide 14.7 g (74%) of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio-1H-imidazole; mp 72°-74°C.

(ii) 1-(2-chlorophenyl)methyl-5-carboxymethyl-2-propylthio-1H-imidazole

A mixture of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-thio-1H-imidazole (2 g, 7.08mmol), ethyl acetate (20 mL), 5% sodium carbonate solution (40 mL) andpropyl bromide (4 mL, 44 mmol) was heated at 60° C. for 18 hours. Theorganic layer was separated, dried over magnesium sulfate andconcentrated to 2.23 g of crude product. Trituration with diethyl etherprovided 1.63 g (71%) of5-carboxymethyl-1-(2-chlorophenyl)-methyl-2-propylthio-1H-imidazole; mp68°-71° C. (from hexane).

(iii) 1-(2-chlorophenyl)methyl-5-chloromethyl,2-propylthio-1H-imidazole

A solution of5-carboxymethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (3.74g, 11.5 mmol) in dry tetrahydrofuran (50 mL) was cooled to -78° C. underargon, and a solution of diisobutyl aluminum hydride in toluene (30 mLof 1M) was added dropwise. The mixture was stirred at -78° C. for 1.5hours, then allowed to slowly warm to room temperature, The reaction wasquenched by pouring onto iced dilute acetic acid, the product wasextracted into methylene chloride, and the organic extracts were washedwith water, 5% sodium carbonate solution and brine. The dried,concentrated product was a light tan solid (3.32 g). Crystallizationfrom ethanol/watergave-1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole;mp 98°-101° C.

A mixture of1-(2-chlorophenyl)methyl-5-hydroxy-methyl-2-thiopropyl-1H-imidazole (10g, 0.0337 mol) in thionyl chloride (75 mL) was refluxed for one hour,evaporated in vacuo and the residue azeotroped three times with toluene.The solid was triturated with diethyl ether and collected to provide10.4 g (88%) of the hydrochloride salt of1-(2-chlorophenyl)methyl-5-chloromethyl-2- propyl-thio -1H-imidazole.

(iv) diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate

To dry dimethylformamide (10 mL) under argon was added sodium hydride(0.14 g, 5.83 mmol) followed by diethyl malonate (0.92 g, 5.75 mmol) indimethylformamide (2 mL) at 0° C. The mixture was stirred at ambienttemperature for one hour. A solution of5-chloromethyl-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazolehydrochloride (1.0 g, 2.84 mmol) in dimethylformamide (4 mL) was addedover 5 minutes. The reaction mixture was stirred at 25° C. for 18 hours,then partitioned between water and methylene chloride. The organic layerwas washed with water, dried, and concentrated. The crude product wasflash chromatographed over silica gel with 1:1 hexane/ethyl acetate togive 0.62 g (49.7%) of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonateas a pale yellow syrup.

(v) 2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-propanoic acid

A solution of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate (0.62 g, 1.41 mmol), sodiumcarbonate (1.5 g, 14.2 mol), ethanol (10 mL) and water (10 mL) wasstirred at 25° C. for 18 hours, then heated for 15 minutes on a steambath. The mixture was cooled, neutralized with aqueous hydrochloric acidsolution, and the product was extracted-into methylene chloride, washedwith water, dried and concentrated to 0.425 g of product.Crystallization from ethyl acetate/hexane provided 0.23 g 55%) of2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid; mp 118°-120° C.

EXAMPLE 43-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoicAcid (i) ethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-ylpropanoate.

Diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-methylmalonate[Example 3 (i) ](0.117 g, 0.285 mmol) was heated neat in air at125°-130° C. for one hour. The title compound (0.14 g) was isolated asan oil.

(ii)3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoicacid

A solution of the above ethyl ester (0.14 g, 0.382 mmol) in 50% aqueousethanol (4 mL) and potassium hydroxide (0.075 g, 1.34 mmol) was stirredat 25° C. for 0.5 hours, water was added, and the mixture wasneutralized with aqueous hydrochloric acid solution. A precipitateresulted. The solid was filtered, washed with water, dried andcrystallized from ethanol to give 70 mg (54%) of3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoicacid; mp 169°-170° C.

EXAMPLE 53-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoic Acid(i) 2-n-butyl-1-(trimethylsilyl)ethoxymethyl-imidazole

Hexane-washed 80% sodium hydride (1.45 g, 0.0483 mol) indimethylformamide (80 mL) under argon was treated with a solution of2-n-butylimidazole (5.45 g, 0.0439 mol) in dimethylformamide (14 mL)dropwise at 25° C., and the reaction was stirred an additional hour.Then, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl) (7.68 g, 0. 0461mol) was added, the mixture was stirred for 18 hours at ambienttemperature and then partitioned between ice water and ethyl acetate.The washed, dried, concentrated organic solution was flashchromatographed over silica gel with 1:1 hexane in ethyl acetate toyield 10.8 g (96%) of2-n-butyl-1-(trimethylsilyl)ethyoxymethyl-imidazole.

(ii) 2-n-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole

A solution of 2-n-butyl-l-SEM imidazole (prepared above) (6.37 g, 0.025mol) in diethyl ether (125 mL) was treated dropwise with n-butyl lithium(0.0255 mol, 10.2 mL of 2.5M in hexane) under argon at room temperature.After being stirred for an additional 45 minutes, tributyltin chloride(8.83 g, 7.4 mL, 0.026 mol) was added dropwise. The suspension wasstirred overnight, saturated ammonium chloride solution was added, andthe ether layer was separated, washed with brine, dried over sodiumsulfate, concentrated and flash chromatographed over silica gel with 3:1hexane/ethyl acetate to provide 11.3 g (83%) of2-n-butyl-5-tributyltin-1-(trimethylsilyl)ethoxy-methylimidazole.

(iii) ethyl (E and Z)-3-[2-n-butyl-1-{(trimethylsilyl)-ethoxymethyl}-1H-imidazol-5-yl]-2-propenoate

To a solution ofn-butyl-5-tributyltin-1-(trimethylsilyl)ethoxymethylimidazole (11.3 g,0. 0208 mol) in m-xylene (150 mL) was added ethyl 3-bromopropanoate(4.17 g, 0.0233 mol), followed bytetrakis(triphenyl-phosphine)palladium(O) (0.48 g, 0.416 mmol) . Thereaction mixture was heated at 120° C. for 18 hours under argon. Thecooled mixture was washed with water, 10% ammonium hydroxide solutionand brine. The solution was treated with charcoal and sodium sulfate,filtered, concentrated and flash chromatographed over silica gel with9:1 hexane in ethyl acetate to give 1.96 g (27%) of ethyl(Z)-3-[2-n-butyl-l-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-propenoate as an oil. Further elution with 4:1hexane acetate afforded the E-isomer (1.98 g, 27%) as an oil.

(iv) ethyl3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]propanoate

A suspension of ethyl (E andZ)-3-[2-n-butyl-1-{trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-propanoate(1.10 g, 3.12 mmol) in ethanol (25 mL) and 5% palladium on carbon (700mg) was shaken on a Parr hydrogenation apparatus at 50 psi of hydrogenfor 8.5 hours. The catalyst was filtered, and the filtrate wasconcentrated to 0.992 g (86%) of ethyl3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-propanoate.TLC on silica gel with 7:3 hexane/ethyl acetate gave a single spot withan R_(f) of 0.48.

(v) ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate

A solution of ethyl3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}1H-imidazol-5-yl]propanoate(0.992 g, 2.8 mmol) in ethanol (10 mL) was treated with 5N aqueoushydrochloric acid solution (20 mL), and then the reaction mixture washeated at 60° C. for 3.5 hours. The ethanol was evaporated, and thecooled aqueous solution was basified to pH 8 with 10% aqueous sodiumhydroxide solution. The product was extracted into ethyl acetate, andthe organic extracts were washed with brine, dried with anhydrous sodiumsulfate and concentrated to give 0.314 g (50%) of ethyl3-(2-n-butyl-imidazol-4-yl)-propanoate. This was dissolved in methanol(15 mL) and di-tert-butyldicarbonate (2.44 g, 11.2 mmol) andtriethylamine (1.56 mL, 11.2 mmol) were added. The mixture was stirredfor 18 hours at ambient temperature, the solvent was evaporated, and theresidue was dissolved in hexane and applied to a flash column packedwith silica gel. Elution with 8:2 hexane/ethyl acetate afforded 0.285 g(31%) of ethyl3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate as an oil.

(vi) ethyl 3-[2-n-butyl-1-{(2 -chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate

To a solution of trifluoromethanesulfonic anhydride (163 μL, 0.966 mmol)in methylene chloride (1 mL) held at -75° C. under argon was added2-chlorobenzyl alcohol (138 mg, 0.966 mmol) and diisopropylethylamine(168 μL, 0.966 mmol) in methylene chloride (2 mL) over one minute. Afterbeing stirred for 15 minutes, a solution of ethyl3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate (285 mg,0.878 mmol) in methylene chloride (2 mL) was added over a 3-minuteinterval at -75° C. The reaction mixture was then allowed to warm toroom temperature and was stirred for 18 hours. The solvent wasevaporated, and this crude product was flash chromatographed over silicagel with a gradient of ethyl acetate in hexane to give 179 mg (58%) ofethyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-propanoate asan oil. TLC on silica gel with 1:1 hexane/ethyl acetate showed a singleproduct with an R_(f) of 0.41.

(vii) 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoic acid

A solution of ethyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate (179rag, 0.513 mmol) in ethanol (10 mL) was treated with sodium hydroxide(62 mg, 1.54 mmol) dissolved in water (2 mL). The solution was stirredfor one hour at 25° C., cooled, acidified with 10% aqueous hydrochloricacid solution to pH 4.2 and concentrated to near dryness in vacuo. Water(3 mL) was added, and the resulting white solid was filtered, washedwith water and dried to give 32 mg (20%) of3-[2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate acid;mp 163.5°-164.5° C.

EXAMPLE 6 3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]butyric Acid (i)2-n-butyl-1-(2-chlorophenyl) methyl-1H-imidazole

Imidazole was converted to the 1-diethoxy-orthoamide derivative by themethod of Curtis and Brown, J. Org. Chem., 45, 20 (1980). Imidazole(12.8 g, 0.19 mol) and 118.4 g (0.8 mol) of triethylorthoformate werereacted in the presence of 1 g of p-toluenesulfonic acid to give 20.6(61%), bp 65°-70° C. (0.1 mm) of 1-diethoxy-orthoamide imidazole. Thisproduct (24.0 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250mL), cooled to -40° C. and n-butyl lithium (0.14 mol, 56.4 mL of 2.5M inhexane) was added at -40° C. to -35° C. After 15 minutes, n-butyl iodide(31.1 g, 0.169 mol) was added at -40° C., and the reaction was stirredovernight at ambient temperature. The reaction was partitioned betweendiethyl ether and 0.3N hydrochloric acid, and the organic layer wasrepeatedly extracted with dilute hydrochloric acid. The combined aqueousextracts were neutralized with sodium bicarbonate solution, extractedwith methylene chloride, dried over magnesium sulfate and concentrated.A flash distillation on a Kugelrohr apparatus provided 14.8 g (85%) of2-n-butylimidazole.

2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL)and added dropwise to a solution of sodium methoxide [from sodiumhydride (2.31 g, 0.0934 mol) in methanol(250 mL)]. After one hour, thesolution was evaporated to dryness, and the sodium salt was taken up indry dimethylformamide (150 mL), and 2-chlorobenzyl bromide (16.3 g,0.079 mol) was added. The mixture was heated at 50° C. for 17 hoursunder argon, poured onto ice water, and the product was extracted intoethyl acetate. The extract was washed, dried, and concentrated to give18.5 g of crude product which was flash chromatographed over silica gelwith 2:1 hexane/ethyl acetate to provide 11.9 g (61%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole as an oil. Thin layerchromatography on silica gel with 4:1 hexane/ethyl acetate gave an R_(f)value of 0.59.

(ii) 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole

A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g,0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and aceticacid (60 mL) was heated to reflux for 40 hours under argon. The reactionwas concentrated in vacuo, and the residue was stirred with 500 mL of20% sodium hydroxide solution for 4 hours, diluted with water andextracted with methylene chloride. The extract was washed, dried, andconcentrated. The crude product (117 g) was flash chromatographed over600 g of silica gel with a gradient of ethyl acetate to 10% of methanolin ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixtureof starting material and product, and 44 g (41%) of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl -1H-imidazole; mp86°-88° C. (from ethyl acetate). Further elution provided the bis(4,5-hydroxymethyl) derivative; mp 138°-140° C. (from ethyl acetate).

Method B

A mixture of valeramidine methyl ether hydrochloride (250 g, 1.66 mol)and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia wasallowed to stand overnight at room temperature in a pressure vessel, andthen heated at 65° C. for 4 hours at 375 psi. The ammonia was allowed toevaporate, and the residue was dissolved in methanol (3 L). Theresulting slurry was refluxed with added acetonitrile (1 L). Thesolution was decanted from the solid ammonium chloride while hot. Thisprocedure was repeated, and the combined acetonitrile extracts weretreated with charcoal, filtered hot, and the filtrate was concentratedin vacuo to give the dark oil, 2-n-butyl-5-hydroxymethylimidazole (253g, 1.63 mol, 98%).

This crude alcohol (253 g) was treated with acetic anhydride (400 mL) at-15° C., and then was allowed to warm to ambient temperature withstirring, and then stirred an additional 19 hours. The acetic anhydridewas evaporated at reduced pressure, the residue taken up in methylenechloride, and the organic phase was washed with 5% sodium bicarbonatesolution and water. The extract was dried over sodium sulfate andconcentrated to give 323 g (83%) of 1-acetyl4-acetoxymethyl-2-n-butylimidazole.

This diacetate was N-alkylated by the following procedure. To a solutionof triflic anhydride (120 mL, 0.71 mol) in methylene chloride (200 mL)at -78° C. under argon was added a solution of diisopropyl ethylamine(128 mL, 0.73 mol) and 2-chlorobenzyl alcohol (104 g, 0.72 mol) inmethylene chloride (350 mL) over a period of 20 minutes. After beingstirred an additional 20 minutes at -78° C., this solution was thentreated with 1-acetyl-4-acetoxymethyl-2-n-butylimidazole (146 g, 0.61mol) dissolved in methylene chloride (300 mL) over a 20-minute interval.The mixture was then stirred at ambient temperature for 18 hours, andthe solvents were evaporated.

The residual2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole was usedwithout purification for the hydrolysis of the acetate group.

A solution of crude2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole (250 g)in methanol (200 mL) was treated with 10% sodium hydroxide solution (700mL), and the mixture was heated on a steam bath for 4 hours. Aftercooling, methylene chloride was added, the organic phase was separated,washed with water, dried and concentrated. The residue was dissolved inether, cooled, and seeded to give the crude product. Recrystallizationfrom ethyl acetate gave 176 g of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp86°-88° C. This material was identical in all respects to the productprepared by Method A.

(iii) 2-n-butyl-1- (2-chlorophenyl)methyl-1H-imidazo 1-5-carboxaldehyde

A solution of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g;0.0194 mol) in methylene chloride (25 mL) was added to a suspension ofactivated maganese dioxide (27 g) in methylene chloride (325 mL). Thesuspension was stirred at room temperature for 17 hours. The solids werefiltered, and the filtrate concentrated and flash chromatographed oversilica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde as anoil.

(iv) 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole

A solution of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-5-carboxaldehyde (1.1 g,3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78°C. under argon, and a solution of methyl lithium (3.64 mL of 1.2M indiethyl ether, 4.57 mmol) was added dropwise. The mixture was stirredfor 1.5 hours, quenched with ammonium chloride solution, warmed toambient temperature and extracted with ethyl acetate. The washed, dried,concentrated product was flash chromatographed over silica gel withethyl acetate to provide 1.07 g (92%) of2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole.

(v) [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone

A mixture of2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole (1.07g, 3.65 mmol), activated maganese dioxide (6 g) and toluene (75 mL) washeated at 90° to 100° C. under a slight vacuum with a Dean-Stark waterseparator for 17 hours. The inorganics were filtered, the concentratedfiltrate was applied to a flash silica gel column, and the product waseluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.

(vi) ethyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}1H-imidazol-5-yl]-3-methyl-2-2-propenoate

To absolute ethanol (3 mL) was added freshly cut sodium (55 mg). Thentriethyl phosphonoacetate (0.504 g, 2.16 mmol) and[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]methyl ketone(0,628 g, 2.16 mmol) were added, and the mixture was stirred at 70° C.for 17 hours. The reaction was concentrated, partitioned between ethylacetate and water, and the organic layer was washed with water, dried,concentrated and flash chromatographed to afford 214 mg (27%) of thetitle compound. The NMR was consistent with a trans relationship ofimidazole to the carboxylate group.

(vii) methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]butyrate

A mixture of methyl(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-3-methyl-2-propenoate(165 rag, 0.476 mmol) in methanol (10 mL) and platinum oxide (20 mg) wasshaken under one atmosphere of hydrogen for 3 hours. TLC on silica gelwith 6:4 hexane/ethyl acetate showed a homogenous spot with an R_(f)0.54. The catalyst was filtered, and the filtrate was concentrated to154 mg (93%) of the title compound.

(viii) 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]butyricacid

The procedure of Example 5(vii) was followed using methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]butyrate inplace of ethyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]propanoate. Thetitle compound is a white solid, obtained in 22% yield; mp 131°-133° C.

EXAMPLE 73-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]2-benzylpropanoicAcid (i) Diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2-benzyl-malonate

The procedure of Example 3(iv) was followed using diethylbenzylmalonatein place of diethylmalonate. From 2 g (5.7 mmol) of5-chloromethyl-1-[(2-chlorophenyl)-methyl]-2-propylthio-1H-imidazolehydrochloride and proportional amounts of other reagents, there wasobtained, after silica gel chromatography with hexane/ethyl acetate,2.23 g (74%) of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2-benzylmalonate;mp 88°-89° C. (from hexane).

(ii)3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzyl-propanoicacid

A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2-benzyl-malonate (0.72 gl 1.36mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL)-andethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated,the residual aqueous layer was extracted with diethyl ether, and thebasic solution was adjusted to pH 3.75 with concentrated hydrochloricacid. The precipitated product was extracted into methylene chloride,dried, and concentrated. This crude product was flash chromatographed onsilica gel with 10% methanol in methylene chloride to give 0.51 g (86%)of3-[1-{(2chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoicacid; mp 123°-127° C.

EXAMPLE 83-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-benzylpropanoicAcid (i) 2-n-butyl-1- (2-chlorophenyl)methyl-5-chloromethyl-1H-imidazole

A mixture of2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole [Example6(i)](4.0 g) in thionyl chloride (80 mL) was refluxed for one hour,evaporated in vacuo, and the residue azeotroped three times withtoluene. The solid was triturated with diethyl ether and collected toprovide 3.5 g of the hydrochloride salt of2-n-butyl-1-(2-chlorophenyl)methyl-5-chloromethyl-1H-imidazole.

(ii) diethyl[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonate

The procedures of Example 3(iv) and Example 7 were followed. From 5.51 g(0.022 mol) of diethyl benzylmalonate, 0.53 g (0,022 mol) of sodiumhydride, 50 mL of dimethylformamide and 3.5 g (0.0105 mol) of2-n-butyl-l-(2-chlorophenyl)methyl-5-chloromethyl-1H-imidazolehydrochloride, there was obtained 4.54 g (85%) of the title compound asan oil.

(iii)3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid

The procedure of Example 7(ii) was followed using diethyl[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-2-benzylmalonatein place of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2benzylmalonate.The title compound is a white solid; mp 118°-120° C. (fromacetone/diethyl ether) as the hydrochloride salt.

EXAMPLE 9 Methyl 3-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate

A solution of3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid [Example 8] (0.5 g) was dissolved in methanol (100 mL) and treatedwith excess diethyl ether saturated with dry hydrochloric acid. Themixture was kept at 25° C. for 48 hours. The solvents were evaporated,the residue dissolved in a small amount of methanol. Crystallization wasinduced with diethyl ether. The solid was collected, washed with diethylether, and dried to afford 0.47 g (90%) of the title compound; mp118.5°-120.5° C.

EXAMPLE 103-[2-n-Butyl-4-chloro-1-((2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicAcid (i) methyl3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate

To a solution of methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate[Example 9 (4.34 g, 0.01 mol) in tetrahydrofuran (20 mL) was addedN-chlorosuccinimide (1.35 g, 0.01 mol) in portions over a one hourperiod. The mixture was heated to 60° C. for one-hour. Thetetrahydrofuran was evaporated, the residue was dissolved inethyl-acetate and washed with 5% aqueous sodium bicarbonate solution andwater. The dried, concentrated product was flash chromatographed oversilica gel with 1:1 hexane/ethyl acetate to provide 2.7 g (55%) of thetitle compound.

(ii)3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-propanoicacid

The procedure of Example 4 (ii) was followed using methyl3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzlypropanoate in placeof ethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoate. The title compound isa white solid; mp 138°-139° C. (from acetonitrile).

EXAMPLE 11 3-[2-n-Butyl-1-benzyl-1H-imidazol-5-yl]-2 -benzylpropanoicAcid (i) methyl3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoate

A solution of methyl3-[2-n-butyl-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate[Example 9] (0.75 g) in methanol (25 mL) was stirred with platinum oxide(0.07 g) at room temperature under one atmosphere of hydrogen for 18hours. Column chromatographic separation of the crude product oversilica gel with 10% methanol in ethyl acetate gave 0.52 g of the crudede-chlorinated product. This was further purified on a prep silica gelplate using 30% acetone in hexane to provide 0.125 g of methyl3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoate as a syrup.

(ii) methyl 3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoicacid

A mixture of methyl3-[2-n-butyl-1-benzyl-1H-imidazol-5yl]-2-benzylpropanoate (0.12 g, 0.31mmol) in 50% aqueous ethanol (4 mL) containing potassium hydroxide(0.072 g, 1.28 mmol) was stirred at 25° C. for 18 hours. The basicsolution was diluted with water (8 mL), and extracted with diethylether. The water solution was acidified with aqueous hydrochloric acidsolution to pH 4, and the product was extracted into methylene chloride,dried, and concentrated. This crude material was dissolved in acetoneand acidified with ethereal hydrochloric acid to give a precipitate.Crystallization from acetone/ether provided 0.07 g of3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp148°-150° C. (hydrochloride salt).

EXAMPLE 12[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylmalonicAcid

A solution of diethyl[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonate [Example 8(iii)] (5.54 g, 0.0108 mol) in ethanol (75 mL) wastreated all at once with a solution of potassium hydroxide (3.65 g,0.065 mol) in water (50 mL). The resulting mixture was stirred at roomtemperature for 24 hours, then refluxed for 3 hours. The ethanol wasevaporated, water was added to the aqueous product, and the basicsolution was extracted with diethyl ether. The aqueous layer wasacidified to pH 4 with hydrochloric acid and the product was extractedinto ethyl acetate. The dried, concentrated product was crystallizedtwice-from ethyl acetate to give 0.6 g of2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonicacid; mp 165°-166° C.(d). The filtrates from the crystallizations (4.9g) consisted of additional malonic acid, the propanoic acid derivativeand the mono ethyl ester malonate derivative. These are converted to [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid by the method described previously.

EXAMPLE 13 3-[{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-(2-propenyl)propanoicAcid

The procedure of Example 8 was followed using diethyl(2-propenyl)malonate in place of diethyl benzyl-malonate. From 2.8 g(0.014 mol) of diethyl (2-propenyl)-malonate, 2 g (0. 0057 mol) of5-chloromethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazolehydrochloride (Example 3) and proportional amounts of the otherreagents, there was obtained, after heating the derived free malonicacid at 170° C. for 1 hour and flash chromatography over silica gel with5% methanol in methylene chloride, 0.281 g of 3-[{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-(2propenyl)propanoic acid; mp121°-122° C.

EXAMPLE 143-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoicAcid (i) methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propanoate

A mixture of methyl (E andZ)-3-[2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propenoatehydrochloride salt (prepared by the method in Example 6, replacingmethyl lithium with butyl lithium) (245 mg, 0.578 mmol) in methanol (15mL) and platinum oxide (30 mg) was stirred under an atmosphere ofhydrogen for 0.5 hours. The catalyst was filtered, the filtrate wasconcentrated, and the residue was triturated with diethyl ether toafford 181 mg (74%) of methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoatehydrochloride; mp 123°-125° C.

(ii)3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoicacid

A mixture of methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propanoatehydrochloride (181 mg, 0,423 mmol) in ethanol (10 mL) was stirred with10% aqueous sodium hydroxide solution (2 mL) for 18 hours. The pH wasadjusted to pH 1.5 and the product was extracted into methylenechloride, washed with water, dried over anhydrous sodium sulfate andconcentrated to an oil. Trituration with diethyl ether and chilling gavea first crop of 25 mg of the hydrochloride salt of3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoicacid; mp 128°-130° C.

EXAMPLE 153-[1-{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-n-pentylpropanoicAcid (i)diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-n-pentyl-malonate

The procedure of Example 3(iv) was followed using diethyln-pentylmalonate in place of diethyl malonate. The product was purifiedover silica gel with 10% ethyl acetate in hexane to provide the titlecompound as a syrup in 29.5% yield.

(ii)3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-n-pentyl-propanoicacid

A solution of diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-n-pentylmalonate(0.86 g, 1.69 mmol) in ethanol (20 mL) was stirred with a solution ofpotassium hydroxide (0.38 g, 6,8 mmol) at reflux for 12 hours. Themixture was diluted with water and extracted with diethyl ether. Theaqueous layer was acidified with 10% aqueous hydrochloric acid solutionand the product was extracted into ethyl acetate. The organic extractwas dried and concentrated to give 0.68 g of predominately the freemalonic acid intermediate. This was heated in an oil bath at 170° C. forone hour. The residue was flash chromatographed over silica gel elutingwith 5% methanol in methylene chloride to afford 0.235 g (34%) of3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-n-pentylpropanoic acid;. mp 122°-124° C. (hydrochloride salt).

EXAMPLE 163-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-pentylpropanoicAcid

The title compound was prepared by the method described in Example 14(i-ii); mp 124°-127° C. (hydrochloride salt).

EXAMPLE 174-[1{(2-Chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]butyric Acid(i)5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazole

Diethyl[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]malonate wasconverted to2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]acetic acidby the method described in Example 15. The methyl ester was prepared inmethanol/hydrochloric acid to give methyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5yl]acetatehydro- chloride; mp 158°-159° C.

A solution of methyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]acetate (2.1g, 6.2 mmol) in dry tetrahydrofuran (150 mL) was cooled to -78° C. for1.5 hours and at ambient temperature for 1 8 hours. Methanol was addedfollowed by 5% aqueous acetic acid. The mixture was concentrated invacuo, the residue was extracted with methylene chloride, and theorganic extract was washed with 5% aqueous sodium carbonate solution,dried, and concentrated to give 2.33 g of crude product. This waschromatographed over silica gel with ethyl acetate to give 1.6 g (84%)of1-[(2-chlorophenyl)methyl]-5-(2-hydroxy)ethyl-2-propylthio-1H-imidazoleas an oil.

A mixture of1-[(2-chlorophenyl)methyl]-5-(2-hydroxy)-ethyl-2-propylthio-1H-imidazole(0.1 g) was stirred with thionyl chloride (1 mL) for 30 minutes at 25°C. and then refluxed for 15 minutes. The reaction was concentrated atreduced pressure and azeotroped several times with dry toluene. Theresidue was triturated with diethyl ether to give 80 mg (68%) of5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazolehydrochloride; mp 133°-134° C.

(ii) diethyl2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]ethylmalonate

The procedure of Example 3(iv) was followed using5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazolehydrochloride in place of5-chloromethyl-1-[(2chlorophenyl)methyl]2-propylthio-1H-imidazolehydrochloride. The title compound was obtained in 71% yield afterchromatography over silica gel with a gradient of ethyl acetate inmethylene chloride.

(iii) 4[1-{(2-chlorophenyl/methyl-2-propylthio-1H-imidazol-5-yl]butyricacid

The procedure of Example 15(ii) was followed using diethyl2-[1-{(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]ethylmalonatein place of diethyl[1-{(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]methyl-n-pentylmalonate.The title compound is a white solid obtained in 64% yield; mp 98°-99° C.(from acetonitrile).

EXAMPLE 185-[2-n-Butyl-1-{(2-chlorophenyl)methyl-1H-imidazole-5-yl]pentanoic Acid(i) methyl5-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]pentanoate

(E,E)-5-[2-n-butyl-1{(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2,4-pentadienoicacid (mp 219°-220° C., prepared from2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde [Example6 (iii) ], triethyl 4-phosphonocrotonate, and sodium hydride in glyme,followed by base hydrolysis) was converted to the methyl esterhydrochloride with hydrochloric acid in methanol, and this diene methylester (0.12 g) was hydrogenated in methanol (20 mL) in the presence ofplatinum oxide (15 mg) and one atmosphere of hydrogen for one hour. Thecatalyst was filtered and the concentrated filtrate was chromatographedover silica gel with 3:1 ethyl acetate/hexane to provide 0,073 g (61%)of methyl 5-[2-n-butyl-l-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]pentanoate.

(ii) 5-[2-n-butyl-1-{(2-chlorophenyl)methyl1H-imidazol-5-yl]pentanoicacid

The precursor methyl ester was hydrolyzed to the free acid with aqueousbase by the procedure of Example 5 (vii) to provide5-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5yl]pentanoic acid;mp 95°-97° C. (hydrochloride salt).

EXAMPLE 196-[2-n-Butyl-1-{2-chlorophenyl)methyl}-1H-imidazol-5-yl]hexanoic Acid(i) 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-hexenoicacid

To a suspension of (4-carboxybutyl)triphenyl-phosphonium bromide (1.04g, 2.35 mmol) in dry tetrahydrofuran (25 mL) at 0° C. under argon wasadded n-butyl lithium in hexane (1.8 mL of 2.5M, 4.6 mmol). The reactionmixture was stirred for 15 minutes at 0° C. and then a solution of2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde [Example6 (iii)] (0.5 g, 1.81 mmol) in tetrahydrofuran (25 mL) was addeddropwise. The mixture was stirred an additional hour at 0° C. and thenat ambient temperature for 3 days. Water was added and the mixture wasextracted with diethyl ether. The aqueous layer was acidified to pH 3with aqueous hydrochloric acid solution. The product was extracted intoethyl acetate, washed with water, dried, concentrated, andchromatographed over silica gel eluting with 5-10% methanol in methylenechloride to give 0.24 g of6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-hexenoicacid.

(ii) 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]hexanoicacid

6-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-4-hexenoic acidwas converted to the methyl ester with methanol and etherealhydrochloric acid. This methyl ester (302 mg) in methanol washydrogenated with platinum oxide (25 mg) at one atmosphere of hydrogenfor 2 hours. The isolated crude reduced ester was chromatographed oversilica gel with 3:1 ethyl acetate/hexane to provide 0.125 g of methyl6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]hexanoate. Basichydrolysis of this ester with potassium hydroxide as described inExample 11(ii) provided 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-hexanoic acidhydrochloride; mp 144°-145° C. (from acetone).

EXAMPLE 20 (2RS,3SR)-3-[2-n-Butyl-1-{(2-chlorophenyl)methyl-1H-imidazol5-yl]-2-benzyl-3-methylpropanoicAcid (i) ethyl (2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl)-1H-imidazol-5-yl]2-benzyl-3-methylpropanoate

A suspension of ethyl(E)-3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]-2-benzyl-3-methyl-2propenoate(1.59 g, 3.73 mmol), prepared by the method described in Example 5 usingethyl 3-bromo-2-benzyl-2-propenoate in place of 3-bromopropenoate, inethanol (25 mL) with 5% palladium on carbon was reduced on the Parrhydrogenation apparatus at 40 psi of hydrogen for 8 hours. The isolatedcrude product was flash chromatographed over silica gel with a gradientof 6:1 to 4:1 hexane in ethyl acetate to afford 1.36 g (85%) of ethyl(2RS,3SR)-3-methylpropanoate as an oil.

A solution of this ester (1.36 g, 3.17 mmol) in methylene chloride wasadded at -78° C. to a solution prepared by the addition at -78° C. underargon of 2-chlorobenzyl alcohol (0.559 g, 3.88 mmol) and di- isopropylethylamine (0.83 mL) to trifluoromethanesulfonic anhydride (0.64 mL) inmethylene chloride (40 mL). The reaction was allowed to warm to ambienttemperature and was stirred for an additional 22 hours. A solution of 5%aqueous sodium bicarbonate solution was added, and the layers wereseparated, washed, and dried. The crude product was chromatographed oversilica gel with 7:3 hexane/ethyl acetate to yield 1.06 g (74%) of ethyl(2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl-1H-imidazol-5yl]-2-benzyl-3-methylpropanoateas an oil.

(ii)(2RS,3SR)-3-[2-n-butyl-t-{(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-benzyl-3-methylpropanoicacid

A solution of the precursor ethyl ester (1.01 g, 2.23 mmol) wasdissolved in ethanol (12 mL) and 10% aqueous sodium hydroxide solutionwas added. The mixture was refluxed for 24 hours, the ethanol wasevaporated and the aqueous residue was acidified with aqueoushydrochloric acid solution to pH 4. The product, was extracted intoethyl acetate, washed with water, dried, and concentrated. The crudematerial (898 mg) was dissolved in a small amount of ethyl acetate,diethyl ether was added and the chilled mixture deposited 423 mg (45%)of (2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)-methyl-1H-imidazol-5-yl]-2-benzyl-3-methylpropanoic acid; mp 216°-218°C.

EXAMPLE 213-[2-n-Butyl-1{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoicAcid

2-n-Butyl-1-[(4-carbomethoxyphenyl)methyl]-1H-imidazol-5-carboxyaldehyde(6.07g, 0.202 mol) dissolved in 50 mL of methanol was treatedportionwise with 0.483g (0.0128 mol) of sodium borohydride. Afterseveral minutes the pH of this mixture was brought to 7 with 10% aqueoushydrochloric acid solution, concentrated under vacuum, and water added.The resulting crystals were collected by filtration, washed with water,and dried to give 5.90 g (98%) of the corresponding alcohol, mp141°-143° C. Thionyl chloride (7.5 mL) was added to 1.51 g (0.00499 mol)of the alcohol and the mixture heated on a steam bath for 45 minutes.Concentration under vacuum gave a syrup which was treated with 30 mL ofether and the ether removed under vacuum. Repetition of theether-evaporation cycle times gave a solid which was taken up in 10 mLof methylene chloride and the solution added to ether to give 1.76g(99%) of the chloromethyl imidazole hydrochloride, mp 151°-153° C.

Diethyl 2-thienyl-methylmalonate (2.68 g, 0.1245 mol) was added dropwiseto a stirred suspension of 0.245 g (0.0102 mol) of sodium hydride in 25mL of anhydrous dimethylformamide at ambient temperature under argon.After 2 hours a solution of 1.76 g (0.006 mol) of the chloromethylimidazole hydrochloride in 10 mL of dry dimethylformamide was added andthe mixture stirred 18 hours. The precipitated salt was removed byfiltration and washed with ether. The combined filtrates were extractedfour times with 25 mL portions of 6N aqueous hydrochloric acid solution,the aqueous treated with 50% sodium hydroxide to bring the pH to 9.5 andthen extracted with ether. Concentration of the dried ether under vacuumgave 2.28 g (84%) of the triester as a syrup.

A mixture of 1.03 g (0.019 mol) of the triester and 25 mL of 12Nhydrochloric acid was refluxed for 24 hours. The reaction mixture wasconcentrated to dryness under vacuum and triturated with ether to give0.88 g of product as the hydrochloride. This was dissolved in water, thesolution brought to pH 10 with 10% aqueous sodium hydroxide solution,filtered, and the pH brought to 4 with 6N hydrochloric acid. The solidwhich formed was collected by filtration, washed with water, and driedto give 0.53 g (65%) of the title compound; mp 175° C., softens 125° C.

EXAMPLE 223-[2-n-Butyl-1-{4-carboxyphenyl)methyl}-4-chloro]-1H-imidazol-5-yl]-2-{2-thienylmethyl)propanoic Acid

The title compound was prepared following the procedure of Example 21using2-n-butyl-1-[(4-carbomethoxyphenyl)-methyl]-4-chloro]-1H-imidazol-5-carboxaldehyde;mp 112°-115° C.

EXAMPLE 233-[2-n-Butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicAcid

The title compound was prepared following the procedure of Example 21using2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]-1H-imidazol-5-carboxaldehydeand diethyl benzylmalonate; mp 120°-124° C.

EXAMPLE 243-[2-n-Butyl-1-{4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(4-chlorobenzyl)propanoic Acid

A mixture of2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]-1H-imidazol-5-carboxaldehyde(5.0g, 0.0167 mol), diethyl malonate (2.85g, 0.0178 mol), piperidine(0.22 mL) and benzoic acid (4.3 mg) in 40 mL of benzene was refluxedunder argon for 25 hours using a Dean-Stark trap to remove water. Themixture was washed in turn with saturated aqueous sodium bicarbonate,water, and saturated brine, and then concentrated under vacuum to give7.93 g of a syrup. Flash chromatography on silica gel of 23.37 g ofsyrup eluting with 1:1 ethyl acetate-hexane gave 18.86 g of pure diesteras an oil.

Sodium borohydride (0.80 g, 0.211 mol) was added in portions to astirred solution of 17.86 g (0.040 mol) of diester in 50 mL of ethanolcooled in an ice bath. Addition of 10% aqueous hydrochloric acidsolution to bring the pH to 7 was followed by evaporation to drynessunder vacuum, partition of the residue between ether and water, andextraction of the aqueous layer with fresh ether. The combined etherextracts were washed in turn with water and brine, dried, andconcentrated under vacuum to give 17.86 g (99%) of malonate as a syrup.

A solution of 1.37 g (0.00308 mol) of the malonate in 10 mL ofdimethylformamide was added to a stirred suspension of 0.080 g (0.0034mol) of sodium hydride in 10 mL of dry dimethylformamide under argon.After stirring the mixtures for one hour 0.54 g (0.0034 mol) of4-chlorobenzylchloride in 5 mL of dimethylformamide was added and thestirring continued for 7 hours. The mixture was then poured into 150 mLof water and extracted 3 times with 400 mL of ether. The ether extractwas washed with water and then brine, and concentrated under vacuum togive 1.64 g (94%) of the 4chlorobenzyl malonate as a syrup. Flashchromatography on silica gel (7:3 ethyl acetate-hexane) gave 1.25 g(71%) of purified product as an oil. This was dissolved in a solution of0.97 g of sodium hydroxide in 40 mL of 1:1 ethanol-water and stirred for18 hours. The mixture was then heated on a steam bath for 1 hr to removemost of the ethanol, diluted with 20 mL of water, filtered, and the pHadjusted to 3.4 with 10% hydrochloric acid. The resulting solid wascollected by filtration and washed to give 1.04 g of a solid; mp 119°C.; sublimed, mp 210° C. The product was refluxed in 30 mL of 12Nhydrochloric acid for 18 hours and this mixture evaporated to give afoam. This was dissolved in ethanol, filtered, and concentrated undervacuum to a foam. This process was repeated to give 0.89 g (81%) ofcrystals of final product; mp 151°-156° C. (ethanol-ethyl acetate).

EXAMPLE 25 3-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]-2-(4-methoxybenzyl)propanoic Acid

The title compound was prepared following the procedure Example 24 using4-methoxybenzylchloride.

EXAMPLE 26

The following compounds are prepared using the procedures hereinbeforedescribed:

3-[2-n-butyl-1-{(4-carboxy-2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-butyl-1-{(4-carboxy-3-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-butyl-1-{(4-carboxy-2,3-dichlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-propyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid,

3-[2-n-hexyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid,

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5yl]-2-(3-thienylmethyl)propanoicacid,

3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5yl]-2-(2-furylmethyl)propanoicacid, and

3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5yl]-2-(2-thienylmethyl)propanoic acid.

EXAMPLE 27

An oral dosage form for administering orally active Formula (I)compounds is produced by screening, mixing and filling into hard gelatincapsules the ingredients in proportions, for example, as shown below.

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        3-(2-n-butyl-1-{(2-      100 mg                                               chlorophenyl)methyl}-1H-imidazol-5-                                           yl]-2-benzylpropanoic acid                                                    magnesium stearate        10 mg                                               lactose                  100 mg                                               ______________________________________                                    

EXAMPLE 28

The sucrose calcium sulfate dihydrate and orally active Formula (I)compounds are mixed and granulated with a 10% gelatin solution. The wetgranules are screened, dried, mixed with the starch, talc and stearicacid, screened and compressed into a tablet.

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        2-n-butyl-1-{(2-chlorophenyl)methyl                                                                     75 mg                                               1H-imidazol-5-yl]-2-n-butylpropanoi                                           acid                                                                          calcium sulfate dehydrate                                                                              100 mg                                               sucrose                   15 mg                                               starch                    8 mg                                                talc                      4 mg                                                stearic acid              2 mg                                                ______________________________________                                    

EXAMPLE 293-[2-n-Butyl-1-{(chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid, 50 mg, is dispersed in 25 mL of normal saline to prepare aninjectable preparation. EXAMPLE 30

A topical ophthalmological solution for administering Formula (I)compounds is produced by mixing under sterile conditions the ingredientsin proportions, for example, as shown below.

    ______________________________________                                        Ingredients          Amounts (mg/mL                                           ______________________________________                                        2-n-butyl-1-{(2-chlorophenyl)methy                                                                 1.0                                                      1H-imidazol-5-yl]-2-n-butylpropano                                            acid                                                                          dibasic sodium phosphate                                                                           10.4                                                     monobasic sodium phosphate                                                                         2.4                                                      chlorobutanol        5.0                                                      hydroxypropanol methylcellulose                                                                    5.0                                                      sterile water        q.s. ad 1.0 ml                                           1.0N sodium hydroxide                                                                              q.s. ad pH 7.4                                           ______________________________________                                    

It is to be understood that the invention is not limited to theembodiments illustrated hereabove, and the right to the illustratedembodiments and all modifications coming within the scope of thefollowing claims is reserved.

What is claimed is:
 1. A compound of the formula: ##STR13## in which: R¹is adamanthylmethyl, or phenyl, biphenyl, or naphthyl, with each arylgroup being unsubstituted or substituted by one to three substituentsselected from Cl, Br, F, I, C₁₋₆ alkyl, nitro CO₂ R⁸, tetrazol-5-yl,C₁₋₆ alkoxy, hydroxy, SC₁₋₄ alkyl SO₂ NHR⁸, NHSO₂ R⁸, SO₃ H, CONR⁸ R⁸,CN, SO₂ C₁₋₄ alkyl, or C_(n) F_(2n+1), wherein n is 1-3;R² is C₂₋₁₀alkyl, C₃₋₁₀ alkenyl, C₃₋₁₀ alkynyl, C₃₋₆ cycloalkyl, or (CH₂)₀₋₈ phenylunsubstituted or substituted by one to three substituents selected fromC₁₋₆ alkyl, nitro, Cl, Br, F, I, hydroxy, C₁₋₆ alkoxy, NR⁸ R⁸, CO₂ R⁸,CN or CONR⁸ R⁸ ; X is a single bond, S, or O; R³ is hydrogen, Cl, Br, F,I, CHO, hydroxymethyl, CO₂ R⁸, NO₂, or C_(n) F_(2n+1), wherein n is 1-3;q is 0 to 4; m is 0 to 2; R⁴ is H or C₁₋₆ alkyl; z is 0 to 1; R⁵ is C₃₋₆alkenyl, phenyl-Y-, 2- or 3- thienyl-Y-, 2-or 3-furyl-Y-, 2-, 3-, or4-pyridyl-Y-, tetrazolyl-Y-, triazolyl-Y-, imidazolyl-Y-, pyrazolyl-Y-,thiazolyl-Y-, pyrrolyl-Y-, or oxazolyl-Y-, with each aryl ring beingunsubstituted or substituted by C₁₋₆ alkyl, Cl, Br, F, I, C₁₋₆ alkoxy,NR⁸ R⁸, CO₂ R⁸, or CONR⁸ R⁸ ; Y is a single bond or C₁₋₆ alkyl which isbranched or unbranched; R⁶ is CO₂ R⁸, CONR⁸ R⁸, or tetrazol-5-yl; R⁷ isH, CO₂ R⁸, or C₁₋₆ alkyl; and each R⁸ independently is hydrogen, C₁₋₆alkyl, or (CH₃)₀₋₄ phenyl;or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 in which:R¹ is phenyl unsubstituted orsubstituted by one to three substituents selected from chloro, fluoro,trifluoromethyl, nitro, methyl, methoxy, hydroxy, sulfonamido, cyano,carboxy, carboC₁₋₆ alkoxy, carbamoyl, or tetrazol-5-yl; q is one; X is asingle bond or S; R² is C₂₋₈ alkyl; R³ is hydrogen, chloro, fluoro, orC_(n) F_(2n+1), wherein n is 1-3; and R⁵ is phenyl-CH₂ -, or thienyl-CH₂--, with each aryl ring being unsubstituted or substituted by methyl,methoxy, or chloro;or a pharmaceutically acceptable salt thereof.
 3. Acompound of claim 2 which is3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid or a pharmaceutically acceptable salt thereof.
 4. A compound ofclaim 2 which is3-[2-n-butyl-1-{(4carboxyphenyl)methyl}1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoicacid; or a pharmaceutically acceptable salt thereof.
 5. A compound ofclaim 2 whichis:3-[2-n-butyl-1-{(2-chlorophenyl)methyl}1-H-imidazol-5yl]-2-benzylpropanoicacid;3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5yl]-2-(4-chlorobenzyl)propanoicacid; 3-[2-n-butyl-1-{4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoic acid;3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid; (2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-3-methyl propanoic acid; 3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2benzylpropanoic acid;2-carboethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid;3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoic acid;3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazolyl5-yl]-2-(2-propenyl)propionic acid;2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylmalonic acid; or methyl3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol -5-yl]-2-benzylpropionate;or a pharmaceutically acceptable salt thereof.
 6. Apharmaceutical composition comprising a compound of claim 1 and asuitable pharmaceutical carrier.
 7. A pharmaceutical composition ofclaim 6 wherein the compound is3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid or a pharmaceutically acceptablesalt thereof.
 8. A pharmaceutical composition of claim 6 wherein thecompound is 3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}1H-imidazol-5-yl]-2-(2-thienylmethyl)propanoic acid; or a pharmaceuticallyacceptable salt thereof.
 9. A pharmaceutical composition of claim 6wherein the compoundis:3-[2-n-butyll-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoicacid; 3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-(4-chlorobenzyl)propanoic acid; 3-[2-n-butyl-1-{4-carboxyphenyl)methyl}-4-chloro-1H-imidazol-5-yl]-2-(2-thienylmethyl) propanoic acid;3-[2-n-butyl-4-chloro-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid; (2RS,3SR)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-3-methylpropanoic acid;2-carboethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid;3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol--yl]-2-benzylpropanoic acid;3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol--yl]-2-n-pentylpropanoic acid;3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol--yl]-2-(2-propenyl)propionic acid;2-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazo 1-5-yl]-2-benzylmalonic acid; or methyl3-[2-n-butyl-1-{(2-chlorophenyl)-methyl}-1H-imidazol-5-yl]-2-benzylpropionate.
 10. A method of treating hypertensionin mammals which comprises administering to a subject in need thereof aneffective amount of a compound of claim 1.